Behavioral and biochemical evidence for a nonessential 5-HT2A component of the ibogaine-induced discriminative stimulus.
In the present investigation, the ability of two known hallucinogens, lysergic acid dimethylamide (LSD) and (-)-2,5-dimethoxy-4-methyl-amphetamine (DOM), to substitute for the ibogaine-induced discriminative stimulus (10 mg/kg I.P., 60 min presession) was assessed in Fischer-344 rats. In these subjects, intermediate levels of generalization were observed to both agents (LSD, 63%; DOM, 66.4%). This intermediate generalization was completely blocked by pretreatment with the 5-HT2A antagonist pirenpirone, suggesting that the ibogaine-like effects of these agents are mediated by the 5-HT2A receptor. However, pirenpirone did not antagonize ibogaine itself, nor did it antagonize the ibogaine-like effects of harmaline and 12-hydroxyibogamine (noribogaine). To further evaluate the serotonergic properties of ibogaine, in vivo protection assays and in vitro binding assays were employed. Micromolar 5-HT2A affinity was observed with ibogaine (92.5 microM), 12-hydroxyibogamine (34.5 microM), and harmaline (42.5 microM). Despite the apparently low affinity of these agents, both ibogaine and harmaline, but not 12-hydroxyibogamine, produced significant protection from receptor alkylation by N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline (EEDQ) when given 60 min prior to this alkylating agent. The results of these studies suggest that although ibogaine may produce some of its effects via interactions with 5-HT2A receptors, these do not appear to be essential to the ibogaine-induced discriminative stimulus.
Helsley
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S
Department of Pharmacology and Toxicology, School of Medicine and Biomedical Sciences, State University of New York at Buffalo, 14214-3000, USA.
Fiorella
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Rabin
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Winter
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D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine / Q000494:pharmacology; D000477:Alkylating Agents / Q000494:pharmacology; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects*; D004192:Discrimination, Psychological / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D007050:Ibogaine / Q000494:pharmacology*; D007700:Kinetics; D008238:Lysergic Acid Diethylamide / Q000494:pharmacology; D008297:Male; D051381:Rats; D011916:Rats, Inbred F344; D011985:Receptors, Serotonin / Q000187:drug effects*; D012702:Serotonin Antagonists / Q000494:pharmacology
D000477:Alkylating Agents; D006213:Hallucinogens; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D004290:DOM 2,5-Dimethoxy-4-Methylamphetamine; D007050:Ibogaine; D008238:Lysergic Acid Diethylamide